1. Field of the Invention
The present invention relates to a pharmaceutical composition for the prevention and treatment of diabetic complications comprising the extract of Homonoia riparia Lour. or the fraction thereof as an active ingredient.
2. Description of the Related Art
Diabetes mellitus is one of the important adult diseases that concerns us world-widely. Along with the rapid industrial breakthrough, prevalence rate of diabetes reaches 10% recently in Korea and the total diabetes patients in the world are estimated to be at least 240 million, which will be growing to approximately 380 million in 2025.60% of them will be developed in Asia, according to the 2009 report of JAMA. In particular, considering that the diabetes on-set period has been brought forward to middle-aged group and human life-span has been prolonged, it seems hard to avoid many cases of diabetic complications. That is, diabetic complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, heart disease, cancer and osteoporosis are observed generally 10˜20 years after diabetes is taken, during which almost every organ in human body is going to be damaged. Chronic diabetic nephropathy is the major reason of hemodialysis treatment and end-stage renal disease. Diabetic cataract and diabetic retinopathy can cause blindness and even death. The reason of blindness in the age of 25˜74 is diabetes in USA. 60% of diabetes patients experience blindness 15˜20 years after taking diabetes. Therefore, if diabetic complications can be delayed at least 5˜10 years, the quality of life of diabetes patients and their family can be greatly enhanced, which can also be advantageous to national finance.
The mechanism that can cause diabetic complications is explained by nonenzymatic glycation of protein, polyol pathway, and oxidative stress, etc. Nonenzymatic glycation of protein is induced by Maillad reaction, the nonenzymatic condensation of amino acid group such as lysine residue and reducing sugar. Advanced glycation endproducts (AGEs) are produced by this reaction. More particularly, nonenzymatic glycation of protein is carried out by the following steps: (1) amino acid group such as lysine residue and aldehyde or ketone of reducing sugar form the primary product, schiff base, via nonenzymatic nucleophilic addition reaction, and then the produced schiff base is condensated with neighboring ketoamine adduct to produce reversible Amadori type glycation products; and (2) the reversible Amadori type glycation products are not decomposed but rearranged to produce irreversible advanced glycation endproducts under hyperglycemic state, and the produced advanced glycation endproducts are bound to protein or lipid by cross-linking to produce irreversible glycated protein or glycated lipid. Unlike the reversible Amadori type early glycation products, the advanced glycation endproducts are irreversible, indicating that once the advanced glycation endproducts are produced they are not converted even when blood sugar level goes back to normal and instead they are accumulated in tissues as long as the protein or lipid to which the products are conjugated lives to cause abnormal changes in the structures and functions of many tissues, resulting in the complications (Vinson, J. A. et al., 1996, J. Nutritinal Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur. J. Biochem., 210: 729-739). For example, glycated albumin, one of the advanced glycation endproducts produced by the reaction of many kinds of protein and glucose, is a critical reason of chronic diabetic nephropathy. Glycated albumin flows more easily into renal glomerular cells than non-glycated normal albumin, and glucose at high concentration stimulates mesangium cells to increase extracellular matrix synthesis. The excessively influxed glycated albumin and the increased extracellular matrix cause fibrosis of renal glomerulus. Renal glomerulus is continuously damaged by such mechanism, requiring extreme treatment methods such as hemodialysis or organ transplantation. According to the previous reports, as diabetes continues collagen is accumulated as being conjugated with the advanced glycation endproducts in arterial wall and so is basement membrane protein conjugated with the advanced glycation endproducts in renal glomerulus (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632). Such nonenzymatic glycation causes a series of glycations in such proteins as basement membrane protein, plasma albumin, lens protein, fibrin and collagen, and then the produced advanced glycation endproducts induce abnormal changes in the structures and functions of various tissues to cause chronic diabetic complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, etc. In the process of the generation of advanced glycation endproducts under hyperglycemic state, lipid metabolism turns into abnormal and toxic oxygen free-radical is generated, resulting in the decrease of defense system and the increase of oxidative stress (Yokozawa, T., et al, 2001, J. of Trad. Med., 18: 107-112). As explained hereinbefore, nonenzymatic glycation is closely related to oxidative stress mechanism.
Polyol pathway is the process comprising the following steps; (1) Aldose or ketose is reduced into sorbitol by the action of aldose reductase (AR); and (2) The produced sorbitol is oxidized by sorbitol dehydrogenase to produce fructose. In normal condition, aldose reductase has a weak affinity to glucose. However in hyperglycemic state, aldose reductase, the first enzyme of polyol pathway, is over-activated and the excessive blood glucose is converted into sorbitol and fructose which are accumulated in tissues with breaking the balance of osmotic pressure to cause complications. Because of the abnormally increased osmotic pressure, water flows in more, which can progress to diabetic retinopathy, diabetic neuropathy, and diabetic cataract, etc. (Kim, et al., Diabetes, Korean Diabetes Association, Korea Medical Book Publishing, 483; Soulis-Liparota, T., et al., 1995, Diabetologia, 38: 357-394). According to the previous report, the advanced glycation endproducts activate aldose reductase which is the major enzyme of polyol pathway in human microvascular endothelial cells (Nakamura, N., et al., 2000, Free Radic Biol. Med., 29: 17-25). At this time, nonenzymatic glycation of fructose is 10 times faster than that of glucose. Thus, fructose at high concentration is bound with protein to accelerate the production of the advanced glycation endproducts. So, nonenzymatic glycation, polyol pathway, and oxidative stress mechanism are all connected to cause diabetic complications. In the middle of the generation of the advanced glycation endproducts in hyperglycemic state, abnormal changes occur in lipid metabolism and at the same time toxic oxygen free-radical is generated. Then, defense system against such oxygen free-radical is reduced in the course, so that oxidative stress is induced (Yokozawa, T., et al, 2001, J. of Trad. Med., 18: 107-112). That also confirms the interrelation between nonenzymatic glycation and oxidative stress mechanism. Therefore, to delay or prevent or treat diabetic complications, it is important to inhibit the generation of the advanced glycation endproducts (Brownlee, M., et al., 1988, N. Engl. Med., 318, 1315-1321).
Aminoguanidine, the synthetic protein glycation inhibitor, is nucleophilic hydrazine, which is conjugated with Amadori products to prevent cross linking with protein, by which the generation of the advanced glycation endproducts is inhibited to delay or prevent the progress to diabetic complications (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632; Edelstein, D. et al., 1992, Diabetes, 41, 26-29). Aminoguanidine is the synthetic medicine which is the most promising agent so far for the prevention and treatment of diabetic complications and is through the phase III clinical test. However, further clinical test has been canceled because of toxicity induced by the long term administration. Thus, it is required to develop a safer and more efficient natural medicine.
Homonoia riparia Lour. is evergreen shrub belonging to Euphoribiaceae. The height of Homonoia riparia Lour. is 0.5˜3 m and flowers come out in January˜May. Homonoia riparia Lour. is distributed widely in Korea, India, China, Taiwan, and New Guinea, etc. According to Chinese Medicine, it has bitter taste and cold character. It has the medicinal effect of dissipating heat and detoxifying and diuretic effect. However, the pharmacological action and functions of each ingredient of Homonoia riparia Lour., particularly the effect on diabetes or diabetic complications, have not been disclosed, yet.
In the middle of research to develop a safer and more efficient natural drug having no toxicity and side effects for the prevention or treatment of diabetic complications, the present inventors confirmed that The extract of Homonoia riparia Lour. or the fraction thereof had strong activity of inhibiting diabetic complications by suppressing the generations of the advanced glycation endproducts and aldose reductase, in addition to the activity of preventing aging or anti-cancer activity, leading to the completion of this invention.